Cancers can be restored to seeming normality by the addition of cyclic AMP to tumor cells in vitro -- a paradoxical finding, because although some neoplasms are low in cyclic AMP, most have normal levels of this compound. Examining a series of rat hepatomas, we found that a low concentration of cyclic AMP is apparently only one manifestation of low-level, biologically effective cyclic AMP in malignant cells. Other factors which lowered the effective level were diminished binding capacity for cyclic AMP and increased concentration or binding capacity for cyclic GMP (an ofttimes antagonist of cyclic AMP). In particular, we noted that high cyclic GMP levels or enhanced binding yield especially fast-growing tumors. The proposed research has three major aims: 1) to extend pilot studies on cyclic nucleotide binding to larger groups of tumors derived from various cell-types and induced by various viruses and chemicals to determine if our generalizations hold true, and if other generalizations would also apply; 2) to assess the effect of increased cyclic GMP levels on normal and malignant cells in respect to morphology, growth rate and pattern (both in culture and in animal transplants); polynucleotide and protein synthesis; and changes in cell surface; and 3) to discover the causes of altered cyclic nucleotide levels and binding, establish whether inhibition of binding is present, if low levels of binding protein or altered binding protein are implicated, and if diesterases are involved -- then, to isolate the altered cellular components, and finally, determine the prevalence of these changes in tumor cells. And ultimately, we wish to define the role of the altered components in cell metabolism.